New process of preparation of steroids

ABSTRACT

A new process for the preparation of 16 Beta -methyl-17 Alpha hydroxy-1,4,9(11)-pregnatriene-3,20-dione is characterized in that 16 Alpha , 17 Alpha -epoxy-5 Beta -pregnane-3,11,20-trione is reacted with ethylene glycol to form 16 Alpha , 17 Alpha epoxy-3,20-bis-ethylenedioxy-5 Beta -pregnane-11-one, which is reacted with a borohydride to form 16 Alpha ,17 Alpha -epoxy3,20-bis-ethylenedioxy-11 Beta -hydroxy-5 Beta -pregnane, which is reacted with methanesulfonyl chloride to form 16 Alpha ,17 Alpha -epoxy-3,20-bis-ethylenedioxy-5 Beta -pregn-9(11)-ene, which in turn is reacted with a Grignard reagent to form 16 Beta -methyl-17 Alpha -hydroxy-3,20-bis-ethylene-dioxy-5 Beta -pregn9(11)-ene and then with an aqueous acid solution to form 16 Beta -methyl-17 Alpha -hydroxy-5 Beta -pregn-9(11)-ene-3,20-dione which is brominated to form the levo rotatory 1,4-dibromo derivative and then debrominated to form the desired compound.

United States Patent [191 Villax NEW PROCESS OF PREPARATION OF STEROIDS[75] Inventor: Ivan Villax, Lisbon, Portugal [73] Assignee: PlurichemieAnstalt, Vaduz,

Liechtenstein [22] Filed: May 26, 1972 [21] Appl. No.: 257,358

[30] Foreign Application Priority Data June 5, 1971 Portugal 55886 [52]US. Cl. 260/397.45, 260/239.55 C [51] Int. Cl. C07c 169/34 [58] Field ofSearch lMachine Searched Steroids [451 Sept. 25, 1973 PrimaryExaminer--Henry A. French AttorneySidney G. Faber ct al.

[5 7 ABSTRACT A new process for the preparation of l6/3-methyl- 17ahydroxy-l,4,9(1l)-pregnatriene-3,20-dione is characterized in that16a, l7a-epoxy-5/3-pregnane-3,l1,20- trione is reacted with ethyleneglycol to form 16a, 17aepoxy-3,ZO-bis-ethylenedioxy-SB-pregnane-l l-one,which is reacted with a borohydride to form 1601,1701-epoxy-3,20-bis-ethylenedioxy-1 lB-hydroxy-SB- pregnane, which is reactedwith methanesulfonyl chloride to form16a,l7a-epoxy-3,20-bis-ethylenedioxy- 5/3-pregn-9(ll)-ene, which in turnis reacted with a Grignard reagent to form l6B-methyl-l7a-hydroxy-3,20-bis-ethylene-dioxy-SB-pregn-9(ll)-ene and then with an aqueous acidsolution to form l6B-methyl-l 7ahydroxy-5B-pregn-9( l l )-ene-3,20-dionewhich is brominated to form the levo rotatory 1,4-dibromo derivative andthen debrominated to form the desired compound.

10 Claims, No Drawings NEW PROCESS OF PREPARATION OF STEROIDS Sincel6fl-methyl-9a-fluoroprednisolone, commonly known as betamethasone, andits derivatives are today the most active corticosteroidspharmacologically, they are also the most important in their group froma medical point of view.

Amongst the various patents referring to their preparation is U.S. Pat.No. 3,104,246 (1963) which utilizes the 16B-methyll 7a-hydroxy-l ,4,9(1l )-pregnatriene- 3,20-dione of the formula:

:0 ---0H I Y as intermediary compound for the preparation ofbetamethasone. U.S. Pat. No. 3,104,246 also describes a process for thepreparation of said intermediate.

The present invention relates to a process for the preparation ofl6fl-methyl-l7a-hydroxy-l,4,9( l l pregnatriene-3,20-dione through a newpathway which permits high yields, and wherein the number of stepsnecessary to obtain the intermediate is reduced. The process is thusvery economical. In comparison to the process described in U.S. Pat. No.3,104,246, the present process eliminates a few steps includingreacetylation. Although this process utilizes chemical reactions knownper se, these reactions are applied herein to new compounds in a novelsequence which passes through intermediary compounds, most of them newand which are described for the first time in the present specification.

These compounds are valuable for preparing other steroids besidesbetamethasone, thus opening a wider route in the steroid synthesis. Inshort, thepresent invention describes a new and independent process forthe preparation of steroids, particularly of betamethasone and its21-acylates.

The present process uses, as starting compound, the1641,17a-epoxy-fl-pregnane-3J1,20-trione of the for mula:

which was first described by E. Ercoli and P. de Ruggieri, Gazz. Chim.Ital. 85, 1304- (1955). The diketalization at C 3- and C- yields the newcompound 16- 11,1 7a-epoxy-3,20-bis-ethylenedioxy-SB-pregnanel l-one ofthe formula:

l/ j C l epoxy-3 ,20-bis-ethylenedioxy-l lB-hydroxy-SB- pregnane of theformula:

HOW O Subsequently, the dehydration of compound IV by methanesulfonylchloride, containing a catalytic amount of S0,, (or, alternatively,thionyl chloride), yields the new compound 1601,]7a-epoxy-3,20-bis-ethylenedioxy-5B-pregn-9(l l )-ene of the formula:

ii I 1 s When reacting new compound V with a halo-methyl magnesium ingreat excess, the new compound 16B- methyl-l 7a-hydroxy-3,ZO-bis-ethylcnedioxy-5Bpregn- 9(1 1 )-ene of the formula:

CH3 V] l -"OH EOM VI 5 is obtained.

The deketalization of compound VI in an acid medium yields thel6B-methyl-l7a-hydroxy-5B-pregn- 9(1l)-ene-3,20-dione of the formula:

( illa VIII and subsequently debrominating it, or by treating compoundVII directly with 2,3-dihalo-5,6-dicyano-l,4- benzoquinone (DDQ). Thisalternative process yields compound 1 directly from compound VII, thatis, in one step only.

The diketalization is carried out by using excess ethylene glycol, thecatalyst being p-toluenesulfonic acid and the preferred medium anhydrousbenzene, permitting the elimination of water by a Dean-Stark trap,preferably filled with sodium sulfate. The reaction is completed at theend of to 28 hours of reflux. The reaction mixture is subsequentlywashed with a solution of sodium bicarbonate in order to separate theexcess ethylene glycol and the p-toluene-sulfonic acid from the reactionmixture. The benzene phase is dried using anhydrous sodium sulfate andthen evaporated in vacuum. Compound III is crystallized from the residuethus obtained by means of hot methanol containing 1 percent pyridine.The reduction of the ketone function at Cl 1- is carried out by usingsodium or potassium borohydride at the temperature of reflux, the mediumbeing tetrahydrofuran, methanol and water. The reaction is completed atthe end of 3 to 4 hours. Compound IV crystallizes after elimination ofthe organic solvents, under reduced pressure The llB-hydroxy group, thusformed, is eliminated by means of methanesulfonyl chloride giving raiseto a double bond in position 9(1 1 The solvent used preferably is 1lower lto 10 carbon) dialkylformamide such as dimethylformamide, towhich pyridine is added in excess with a view to maintaining thereaction mixture alkaline and thus avoiding the diketalization. With aview to assuring that the reaction is complete, it is necessary toperform same in the presence of a catalytic amount of sulfur trioxide orthionyl chloride.

The addition of methanesulfonyl chloride is made, preferably, at atemperature between l5 and 5 C., then stirring the reaction mixture for3 to 4 hours and allowing it to warm up slowly. The crude product isrecrystallized after precipitation with a mixture of water and icecontaining 0.1 percent pyridine.

The simultaneous introduction of the methyl group in the stericalposition [3 at C16- and of the hydroxyl in the sterical position a at Cl 7- is carried out by using a halo-methyl magnesium, preferablymethylmagnesium bromide, in an inert medium such as tetrahydrofuran anddiethylether, the final concentration of the Grignard reagent being 3 to3.3 X normal, and then refluxing the mixture at a temperature betweenand +95 C., for 15 to 20 hours. After the reaction is completed, themixture is diluted with tetrahydrofuran and then cooled. The excess ofreagent is destroyed by the slow addition of water, yielding the newcompound VI. Alternatively, the excess may be destroyed by addition ofthe reaction mixture to a mixture containing water, ice and hydrochloricacid, yielding directly compound VII. This compound can also be obtainedfrom compound VI by treating its tetrahydrofuran solution with 10percent hydrochloric acid at room temperature, or with 60-70 percentacetic acid at a temperature between +85 and +95 C., for A to 1 hour.

The introduction of the two double bonds at C2- and C4- is carried outaccording to the present invention through two independent pathways atfree choice. The dibromination is performed in such a way as to yieldthe 2a,4fi-levogyre dibromo derivative. The other pathway through DDQfollows the per se known process.

The examples appearing hereafter serve to illustrate the presentinvention, without however limiting its scope.

EXAMPLE 1 PHASE 1 67.5 g of l6a,l7a-epoxy-pregnane- 3,11,20-trione (E.Ercoli and P. de Ruggieri, Gazz. Chim. Ital. 85, I304 (I955) meltingpoint l9420l C.) is refluxed, under stirring, in 3,600 ml benzenecontaining 472.5 ml ethylene glycol and 3.15 g p-toluenesulfonic acid.After refluxing for 19 hours, the condensor being equipped with aDean-Stark trap and containing anhydrous sodium sulfate in thecollector, the reaction is completed which can be verified in analiquot.

After cooling the reaction mixture, it is washed with 675 ml 2N sodiumcarbonate diluted with 2,700 mi water. After separation of the benzenephase, it is dried with anhydrous sodium sulfate and the benzenesolution is concentrated in vacuum until an oil is obtained. Whenmethanol containing 1 percent pyridine is added, the new compound 1601,1 7a-epoxy-3 ,20-bisethylenedioxy-Sfl-pregnane-ll-one (III)crystallizes. Melting point l53-155 C., specific rotation |a| 0 (c l inchloroform). Yield 56 g. When'the motherliquors are collected, a secondfraction containing a satisfactorily pure product is obtained, whichweighs 13.8 g.

Analysis: C II O. Centesimal composition: Calculated:

Found:

Molecular weight: 432.6 C H 0 Analysis: C H O.

Molecular weight: 434.6

Centesimal composition: C H 0 Calculated: 69.1% 8.81% 22.09% Found:68.9% 8.7 22.2

PHASE 3 70 ml methanesulfonyl chloride containing traces of S0 is addeddropwise to 150 g of the product obtained in phase 2 in 750 mldimethylformamide and 200 ml pyridine, at a temperature of C. After theaddition is completed, the reaction mixture is stirred for 5 hours, andthen allowed to warm up slowly. Afterwards, the reaction mixture ispoured into 6,500 ml water and ice containing 0.65 ml pyridine, forminga sticky mass which crystallizes slowly when stirred. Yield 147 g. Afterrecrystallization from methanol containing 1 percent pyridine, 136.6 gof pure product is obtained. The infrared absorption spectrum shows nomaximum in the region of 2.51.4. to 3.2;2.

Molecular weight: 416.6 C H O PHASE 4 (A) 100 g of the product obtainedin Phase 3 is added to 550 ml methylmagnesium bromide 2 to 2.2 N intetrahydrofuran, under a nitrogen atmosphere. The reaction mixture isthen concentrated with a view to obtaining a concentration of theGrignard reagent between 3 to 3.3 normal, and then maintained in refluxfor 18 hours.

Subsequent to reflux, the reaction mixture is cooled to 40 C., 1,200 mltetrahydrofuran is added, and when the temperature is in the rangebetween and C., water is added in such a way as to maintain the mixtureat that temperature. After destruction of the Grignard reagent presentin excess, 2,000 ml water is added, and at least half the amount oftetrahydrofuran is eliminated, under reduced pressure. The16B-methyl-17ahydroxy-3,ZO-bis-ethylenedioxy-SB-pregn-9( 1 l )-enecrystallizes. Yield 99.4 g.

Molecular weight: 432.6 C H O The product thus obtained is thendissolved in 100 ml 70 percent acetic acid and warmed to 90 C., for halfan hour. Afterwards, it is precipitated by the addition of 500 ml water,after which the 16B-methyl-17ahydroxy-5B-pregn-9(1 l )-ene-3,20-dionecrystallizes. After washing with isopropyl ether, a yield of 77.1 g isobtained.

(B) Alternatively, the reaction mixture is cooled and diluted subsequentto reflux, and poured into a mixture of water and ice containing 12percent concentrated hydrochloric acid, followed by the addition of1,000 ml ethylether. After stirring and recycle of the phases thusformed for 2 hours, the organic solvents are eliminated under reducedpressure. The formed crystals are filtered, washed with water and thenwith isopropyl ether. The 16fl-methyl-l 7a-hydroxy-5B-pregn-9(1 1 )-ene-3,20-dione, thus obtained, presents identical physical and chemicalcharacteristics to those of the product described in U.S. Pat. No.3,104,246. Yield 81.2 g. PHASE 5 51.6 ml elemental bromine in 2,630 mlacetic acid is added, under stirring, to 172 g of the product obtainedin Phase 4 (B) in 200 ml dioxane and 2,000 m1 acetic acid containing 1 ganhydrous hydrogen bromide at +5 C., for a period of 25 minutes. It isstirred for 3 hours and then poured into a mixture of 20 liters waterand ice, thus precipitating the 16B-methyl-2a,4fi-dibromo-17a-hydroxy-5B-pregn-9( 1 1 )-ene- 3,20-dione. Theproduct thus obtained is crystallized from isopropyl ether, yielding21.2 g of the levogyre 2,4-dibrominated product.

Analysis: C,,H,.,0,Br Molecular weight: 502.3

Centesimal composition: C Br Calculated: 52.6% 31.82% Found: 52.4% 32.1

PHASE 6 50 g of the debrominated product, obtained according to Phase 5,is then debrominated in 500 m1 dimethylformamide containing g anhydrouslithium carbonate and 50 g anhydrous lithium bromide, by warming to -130C. for minutes. It is cooled and poured slowly into 3 liters water andice containing 200 ml acetic acid. It is filtered, washed and dried.After recrystallization from ethyl acetate and isopropyl ether, 32 g of16B-methyl-l,4,9(11)-pregnatriene-3,20-dione is obtained. The producthas the same physical and chemical characteristics as those describedfor this compound in U.S. Pat. No. 3,104,246.

EXAMPLE 2 100 g of compound V11, obtained in the previous Example inPhase 4 (B), is refluxed in 2 liters dioxane containing 200 g2,3-dichloro-5,6-dicyano-1,4- benzoquinone for 24 hours. The solution iscooled and the crystals, thus formed, are collected. After treating withactive charcoal, the filtrate is concentrated in vacuum. Therecrystallization of the residue, thus obtained, from ethyl acetate andisopropyl ether yields directly 61 g of l6B-methyl-l ,4,9(1 l)-pregnatriene-3,20- dione. Eifi 436 at 240 my. (in ethanol). From thisintermediate betamethasone and its 21-acylates are then prepared inaccordance with the examples of U.S. application Ser. No. 98,202 1970),or according to the examples in, U.S. Pat. No. 3,104,246.

I claim:

1. A new process of preparation of 16B-methy1-17ahydroxyl-1,4,9(l 1)-pregnatriene-3,20-dione comprismg:

a. reacting 16a,17a-epoxy-5fi-pregnane-3,1 1,20- trione with an excessof ethylene glycol in the presence of a solvent thus forming anazeotropic mixture with water and in presence of p-toluenesulfonic acid,yielding the new compound 1601,1701-epoxy-3,20-bis-ethylenedioxy-5fi-pregnanell-one;

b. reacting 1601,]7aepoxy-3,20-bis-ethy1enedioxy- SB-pregnane-l l-onewith sodium or potassium borohydride in an aqueous-organic medium,yielding the new compound 16a,17a-epoxy-3,20-bisethylenedioxy-lIB-hydroxy-SB-pregnane;

c. reacting 1601,17a-epoxy-3,20-bis-ethylenedioxye. reacting in step(d), the temperature of reflux, the concentration of the Grignardreagent being between 3 to 3.3

in step (e), between +l5 and +25 C. when percent hydrochloric acid ispresent and between +85 and +95 C. when acetic acid is present;

in step (f), below +8 C.; and

in step (g), between +l30 and +l38 C.

4. New process according to claim 1 wherein the time 10 of reaction is:

in step (a), from to 28 hours; in step (b), from 3 to 4 hours;

in step (c), from 4 to 5 hours;

in step (d), from 15 to hours; in step (e), from k to l hour;

in step (f), from 1 to 3 hours; and in step (g), from 2 to 3 hours.

solvent or mixture of inert solvents in the presence of a catalyticamount of anhydrous hydrogen bromide in acetic acid, yielding the levorotatory 16/3- 20 methyl-2a,4fl-dibromol 7a-hydroxy-5B-pregn- 9( l l)-ene-3,20-dione; and

g. reacting l6B-methyl-2a,4B-dibromo-l7a-hydroxy- 5fl-prcgn-9(l l)-ene-3,20-dione with a debrominating agent in an organic medium,yielding the desired lofi-methyl-l 7a-hydroxy 1,4,9( 1 lpregnatriene-3,20-dione.

2. New process according to claim 1 wherein the reaction medium is:

5. New process according to claim 1 wherein the tertiary amine in (c) ispyridine.

6. New process according to claim 1 wherein the halo-alkyl magnesium in(d) is methylmagnesium bromide.

7. New process according to claim 1 wherein the aqueous acid in (e) isl0 to l5 percent hydrochloric acid and the solvent is methanol andtetrahydrofuran or 75 percent aqueous acetic acid without any additionalsolvent.

8. New process according to claim 1 wherein the debromination is carriedout with lithium bromide and in step (a), benzene; b t in step (b), amixture of tetrahydrofuran, methanol l mm car ona and water 9. Newprocess according to claim 1 for obtaining l6- B-methyl-17a-hydroxy-l,4,9( l l )-pregnatriene-3,20- dione directly froml6B-methyl-l7a-hydroxy-5B- pregn-9( l l )-ene-3,20-dione, whereinl6B-methyl- 1 7ahydroxy-5fi-pregn-9(ll)-ene-3,20-dione is reacted withan excess of 2,3-dichloro-5,-dicyano-l,4- benzoquinone, or with theequivalent 2,3-dibromoderivative in dioxane and refluxed for 16 to 28hours.

10. l6B-methyl-2a,4B-dibromo-l 7a-hydroxy-5B-pregn-9(11)-ene-3,20-dione.

in step (c), lower dialkylformamide;

in step (d), tetrahydrofuran or lower dialkylether;

in step (e), methanol, tetrahydrofuran or aqueous acetic acid;

in step (f), dioxane or ethyl acetate; and

in step (g), lower dialkylformamide.

3. New process according to claim 1 wherein the reaction temperature is:

in step (a), the temperature of reflux;

in step (b), the temperature of reflux;

in step (c), between l5 and C.;

2. New process according to claim 1 wherein the reaction medium is: instep (a), benzene; in step (b), a mixture of tetrahydrofuran, methanoland water; in step (c), lower dialkylformamide; in step (d),tetrahydrofuran or lower dialkylether; in step (e), methanol,tetrahydrofuran or aqueous acetic acid; in step (f), dioxane or ethylacetate; and in step (g), lower dialkylformamide.
 3. New processaccording to claim 1 wherein the reaction temperature is: in step (a),the temperature of reflux; in step (b), the temperature of reflux; instep (c), between -15* and +45* C.; in step (d), the temperature ofreflux, the concentration of the Grignard reagent being between 3 to 3.3N; in step (e), between +15* and +25* C. when 10 percent hydrochloricacid is present and between +85* and +95* C. when acetic acid ispresent; in step (f), below +8* C.; and in step (g), between +130* and+138* C.
 4. New process according to claim 1 wherein the time ofreaction is: in step (a), from 15 to 28 hours; in step (b), from 3 to 4hours; in step (c), from 4 to 5 hours; in step (d), from 15 to 20 hours;in step (e), from 1/2 to 1 hour; in step (f), from 1 to 3 hours; and instep (g), from 2 to 3 hours.
 5. New process according to claim 1 whereinthe tertiary amine in (c) is pyridine.
 6. New process according to claim1 wherein the halo-alkyl magnesium in (d) is methylmagnesium bromide. 7.New process according to claim 1 wherein the aqueous acid in (e) is 10to 15 percent hydrochloric acid and the solvent is methanol andtetrahydrofuran or 75 percent aqueous acetic acid without any additionalsolvent.
 8. New process according to claim 1 wherein the debrominationis carried out with lithium bromide and lithium carbonate.
 9. Newprocess according to claim 1 for obtaining 16 Beta -methyl-17 Alpha-hydroxy-1,4,9(11)-pregnatriene-3,20-dione directly from 16 Beta-methyl-17 Alpha -hydroxy-5 Beta -pregn-9(11)-ene-3,20-dione, wherein 16Beta -methyl-17 Alpha -hydroxy-5 Beta -pregn-9(11)-ene-3,20-dione isreacted with an excess of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, orwith the equivalent 2,3-dibromo-derivative in dioxane and refluxed for16 to 28 hours.
 10. 16 Beta -methyl-2 Alpha ,4 Beta -dibromo-17 Alpha-hydroxy-5 Beta -pregn-9(11)-ene-3,20-dione.